In U.S. application for Pat. Ser. No. 327,294, filed Jan. 29, 1973, now U.S. Pat. No. 3,894,034 there is described and claimed a process for ortho-alkylating a primary or secondary aromatic amine involving chemical steps comprising reacting an N-halo-aromatic amine with an organic thio-ether to form an azasulfonium salt, reacting the azasulfonium salt with a base to form an ortho-hydrocarbon-S-hydrocarbon aromatic amine thio-ether. If desired, the thio-ether product can be reduced to an ortho-hydrocarbon aromatic amine. This reaction is applicable to both anilines and aminopyridines.
The disclosure of that application and the prior art referred to therein are incorporated herein by reference thereto.
In U.S. application for Pat. Ser. No. 355,198, filed Apr. 27, 1973, now U.S. Pat. No. 3,901,899 there is described and claimed a process for preparing indoles by reacting an N-haloaniline with a .beta.-carbonyl hydrocarbon-S-hydrocarbon sulfide, or an acetal or ketal form thereof, to form an azasulfonium halide salt, and then treating the azasulfonium halide salt with a base to form a thio-ether substituted indole or thio-ether substituted indolenine if a .beta.-carbonyl sulfide or .alpha.-alkyl-.beta.-carbonyl sulfide had been used, respectively, or with a base and then with an acid if a .beta.-carbonyl sulfide acetal or ketal had been used, to form the thio-ether-substituted indole or thio-ether substituted indolenine. Thereafter if desired, the thio-ether indole or thio-ether indolenine can be reduced, e.g., with Raney nickel, to remove the thio-ether group from the indole. The process is applicable to both anilines and aminopyridines.
The disclosure of that application and the prior art referred to therein is incorporated herein by reference thereto.
In the U.S. application Ser. No. 355,207, filed Apr. 27, 1973, now U.S. Pat. No. 3,897,451 there is described and claimed a process for preparing 2-oxindole compounds by reacting an N-haloaniline with a .beta.-thiocarboxylic ester or amide to form an azasulfonium halide salt, treating the azasulfonium halide salt with a base to form an ortho-[1-(thio-ether) (hydrocarbonoxycarbonyl)alkyl]aniline or an ortho-[1-(thio-ether) (aminocarbonyl)alkyl]aniline, and then treating the ortho-substituted aniline with an acid to form a 3-thio-ether-2-oxindole compound. Thereafter, if desired, the 3-thio-ether-2-oxindole can be reduced, e.g., with Raney nickel, to remove the thio-ether group and to form the 2-oxindole.
The disclosure of that application and the prior art referred to therein is incorporated herein by reference thereto.
In the above referenced processes for preparing each of the ortho-alkylated anilines, the indoles, and 2-oxindoles, the azasulfonium halide salt formation step is a common requirement of each process. In continued studies of the above processes it was found that for the preparation of some compounds however, the above process has some limitations. The limitations are associated with the stability of some N-haloanilines when there was present a cation stabilizing group substituent on the aniline ring, e.g. p-methoxyl. The N-chloro-p-anisidines are extremely reactive, even at temperatures as low as -78.degree.C. When using such materials in the above referenced processes to synthesize 4-methoxyanilines, 5-methoxyindoles or 5-methoxy 2-oxindoles respectively, the reactions were difficult to control for the purpose of getting practical yields. Thus, in the development of these chemical processes to practical use in possible commercial operations, there is a need for an alternative process for preparing azasulfonium halide salt intermediates, which process improvement would be particularly useful where highly reactive anilines are to be used.